1. Field of the Invention
The present invention relates to 4'-C-ethynyl nucleosides and the use thereof for producing pharmaceuticals, and more particularly to the use thereof in treating acquired immunodeficiency syndrome (AIDS).
2. Background Art
The clinical setting for AIDS has been dramatically changed by a multi-drug therapy called highly active antiretroviral therapy, or HAART. In this therapy, nucleoside reverse transcriptase inhibitors (NRTIs) such as zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), and lamivudine (3TC) and protease inhibitors (PIs) are employed in combination. Application of this therapy has drastically decreased the number of deaths due to AIDS in many countries (Textbook of AIDS Medicine, p751 (Williams & Wilkins, Baltimore, 1999)).
In spite of the decrease in AIDS-related deaths due to HAART, there has emerged a multi-drug resistant HIV-1 (human immunodeficiency virus-1) mutant exhibiting cross-resistance to various drugs. For example, in the early 1990s patients infected with an HIV exhibiting resistance to both AZT and 3TC were very rare, whereas the percentage of AIDS patients infected with such an HIV was as high as 42% in 1995-1996 (AIDS, 11, 1184(1997)).
It has been reported that such multi-drug resistant viruses cause 30-60% of drug failure cases in which the viremia level drops once below the detection limit and then revives to exhibit lasting viremia (AIDS, 12, 1631(1998)). Thus, the present status of AIDS treatment is serious.
Conventionally, in terms of a compound which exhibits potent antiviral activities against multi-drug resistant viruses, there have been known only a few protease inhibitors; e.g., JE-2147, which have potent antiviral activity against a multi-PI resistant HIV-1 (Proc. Natl. Acad. Sci. USA, 96,8675(1999)). However, no nucleoside derivative having such potent activities has been reported yet.
Ohrui, one of the inventors of the present invention, has synthesized 1-(4-C-ethynyl-.beta.-D-ribopentofuranosyl)thymine, 4'-C-ethynyluridine, and 4'-C-ethynylcytidine and assayed biological activities such as antiviral and antitumor activities thereof. However, no such biological activities have been observed for these compounds (Biosci. Biotechnol. Biochem., 63(4), 736-742, 1999).
Furthermore, Matsuda et al. have synthesized 4'-C-ethynylthymidine and assayed the anti-HIV activity thereof. The anti-HIV activity of the compound is weaker than that of AZT. However, the assay described by Matsuda et al. (Bioorg. Med. Chem. Lett., 9(1999), 385-388) is drawn to an ordinary assay for determining anti-HIV activity on the basis of MT-4 cells versus an HIV-1 III.sub.b strain, and does not use a multi-drug resistant virus strain.